1. Field of the Invention
The present invention is generally related to solid dosage forms of mirtazapine for the treatment of depression and other neurological disorders and diseases.
2. Related Art
Mirtazapine is the common name of the isomeric compound 1, 2, 3, 4, 10, 14β-hexahydro-2-methylpyrazino[2,1-a] pyrido [2,3-c] benzazepine. The use of mirtazapine is well known for the treatment of depression and the symptoms associated with depression including, memory loss, changes in mood, insomnia, lethargy, increase or decrease in weight, and anxiety.
Mirtazapine treats depression by antagonizing the adrenergic 5-HT2A, 5-HT3, and alpha 2 autoreceptors and alpha 2-heteroreceptors, and enhancing the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. It is not known exactly how mirtazapine accomplishes this function. It is also being considered for the treatment of psychotic disorders and diseases such as schizophrenia and movement disorders such as Parkinson's tremors, as disclosed in U.S. Pat. No. 6,281,207. Mirtazapine can be administered alone or with other pharmaceuticals such as selective serotonin reuptake inhibitors (SSRIs), such as those described in U.S. Pat. No. 5,977,099, or antipsychotic agents, such as those described in U.S. Pat. No. 6,150,353.
Mirtazapine has been found to have limited drug interaction and few side effects associated with many antidepressants such as sexual dysfunction. The tetracylic compound is currently manufactured through the methods described in U.S. Pat. No. 4,062,848, forming a racemic mixture of isomeric compounds.
Oral administration in the form of a conventional tablet, pill or capsule constitutes the generally preferred route for administration of pharmaceuticals, such as mirtazapine, since this route is generally convenient and acceptable to patients. Unfortunately such compositions may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who may dislike or have difficulty in swallowing such compositions, or where administration of a conventional tablet, pill or capsule is not feasible. It is highly desirable, particularly in the treatment of acute conditions, that pharmaceutical compositions have a rapid and consistent onset of action combined with sustained activity and good bioavailability.
Since a solid preparation such as an oral tablet requires water for swallowing, a liquid dosage form is normally preferred for the elderly, infants or patients who have difficulty in swallowing. However, a liquid preparation has shortcomings regarding difficulties in handling, especially in measuring an accurate dosage, and that it is not suitable for drugs which are unstable in a moist environment. Thus, an effort has been made to develop a rapidly disintegrating tablet of drugs which can easily disintegrate by the action of saliva.
For example, oral dosage forms have been developed including effervescents which rapidly disintegrate in the mouth and provide taste-masking. See Wehling et al., U.S. Pat. No. 5,178,878. These dosage forms provide significant problems in terms of production, storage, transport and during consumer usage. They are also significantly more costly to produce than conventional tablets.
U.S. Pat. No. 5,178,878 discloses an effervescent tablet which comprises microparticles of various active ingredients. Effervescence is typically created by the formation of gas bubbles upon a reaction of an alkali metal carbonate or carbonate source with an acid or an acid source. The effervescence aids in the complete disintegration of the tablet upon oral administration.
Mirtazapine is currently available in an effervescent oral disintegrating tablet. However, effervescent tablets containing an alkalizing agent are usually moisture sensitive, may be incompatible with an acidic drug and require protection due to their sensitivity to humidity. In addition, the manufacture of effervescent tablets requires strict humidity controls.
Therefore, there is a need for an orally disintegrating tablet of a pharmaceutical composition that does not require an alkalizing agent such as a carbonate or bicarbonate; is compatible with an acidic drug; is physically stable under humid conditions; and is easier to manufacture.